共查询到20条相似文献,搜索用时 31 毫秒
1.
Oliwia Frączak Anika Lasota Anna Leśniak Andrzej W. Lipkowski Aleksandra Olma 《Chemical biology & drug design》2014,84(2):199-205
Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α‐alkylserines in position 2 and 2′. The incorporation of bulky α,α‐disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O,N‐migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor‐binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α‐alkylserine, as analogues containing (R)‐α‐alkylserines displayed higher μ receptor affinity and selectivity than those incorporating the (S)‐isomers. 相似文献
2.
We report the synthesis and binding properties of specific photoaffinity ligands for μ and δ opioid receptor subtypes. These ligands are derived from DAGO: Tyr-D-Ala-Gly-NMePhe-Gly-ol, a μ selective probe and DTLET: Tyr-D-Thr-Gly-Phe-Leu-Thr, a δ selective probe by modifying the Phe 4 residue. These modifications are: i) a nitro group on the para position of Phe ring as Phe(4 NO2) or Nip, ii) an azido group as Phe(4 N3) or AZ. Pharmacological responses on mouse vas deferens (δ sites) and guinea pig ileum (μ sites), as well as competition experiments with [3H] DAGO and [3H] DTLET on crude rat brain membranes have been performed. The nitro group on the phenyl ring of the Phe residue preserves the affinity and selectivity of each probe: NipDAGO for the μ sites, NipDTLET for the δ ones. However the nitro probes do not appear to be photo-activable by u.v. irradiation. Likewise, azidation of the phenyl ring of the Phe residue does not change the receptor selectivity of each probe, but AZDAGO has less affinity than its parent molecule DAGO, while AZDTLET has more affinity than DTLET. These compounds are photoactivable and provide an efficient tool to characterize and isolate the different receptor subtypes, especially the δ site. 相似文献
3.
Irena Berezowska Carole Lemieux Nga N. Chung Brian C. Wilkes Peter W. Schiller 《Chemical biology & drug design》2009,74(4):329-334
The opioid peptide H‐Tyr‐c[D‐Cys‐Phe‐Phe‐Cys]NH2 cyclized via a methylene dithiother is a potent and selective μ opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2′,6′‐dimethyltyrosine (Dmt), 3‐[2,6‐dimethyl‐4‐hydroxyphenyl)propanoic acid (Dhp) or (2S)‐2‐methyl‐3‐(2,6‐dimethyl‐4‐hydroxyphenyl)propanoic acid [(2S)‐Mdp] in the 1‐position were prepared. The peptides were synthesized on solid‐phase by substituting d ‐allylglycine and (2S)‐2‐amino‐5‐hexenoic acid in position 2 and 5, respectively, followed by ring‐closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated –CH2–CH2– bridged peptides. All six Tyr1‐ and Dmt1‐dicarba analogues retained high μ and δ opioid agonist potency and showed only slight or no preference for μ over δ receptors. As expected, the six Dhp1‐ and (2S)‐Mdp1‐dicarba analogues turned out to be μ opioid antagonists but, surprisingly, displayed a range of different efficacies (agonism, partial agonism or antagonism) at the δ receptor. The obtained results indicate that the μ versus δ receptor selectivity and the efficacy at the δ receptor of these cyclic peptides depend on distinct conformational characteristics of the 15‐membered peptide ring structure, which may affect the spatial positioning of the exocyclic residue and of the Phe3 and Phe4 side chains. 相似文献
4.
RALF SCHMIDT BRIAN C. WILKES NGA N. CHUNG CAROLE LEMIEUX PETER W. SCHILLER 《Chemical biology & drug design》1996,48(5):411-419
The β-casomorphin-5 analog H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] (2-Nal = 2-naphthylalanine) was the first reported cyclic opioid peptide with mixed μ agonist/δ antagonist properties [R. Schmidt et al. (1994) J. Med. Chem. 37 , 1136-1144]. The 2-Na13 residue in this peptide was replaced with benzothienylalanine (Bta) (3), His(Bz1) (4), Tyr(Bz1) (5), 4′-benzoylphenylalanine (Bpa) (6), 4′-benzylphenylalanine (Bzp) (7), thyrnine (Thy) (8), thyroxine (Thx) (9), 4′-biphenylalanine (Bip) (10), 4′-biphenylglycine (Bpg) (12) and 3,3-diphenylalanine (Dip) (14), and the in vitro opioid activity profiles of the resulting compounds were determined in μ and δ receptor-representative binding assays and bioassays. Analogues 3, 12 and 14 were full agonists in the μ receptor-representative guinea-pig ileum (GPI) assay and also were agonists in the δ receptor-representative mouse vas deferens (MVD) assay. The agonist effects of the latter compounds in the MVD assay were antagonized by the highly selective δ antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP), indicating that they were triggered by δ receptor activation. The Bzp3- and Bip3-containing peptides 7 and 10 turned out to be μ antagonists against the μ selective agonist H-Tyr-D-Ala-Phe-Phe-NH2, in the GPI assay. The other analogues were weak partial μ agonists which displayed remarkably decreased μ receptor affinity as compared to parent peptide 1. Compounds 4-10 were found to be δ antagonists in the MVD assay. Analogues 4 and 9 exhibited δ antagonist potency similar to that of parent peptide 1, while compounds 5-8 and 10 showed 3-12-fold higher δ antagonist potency against DPDPE and deltorphin I and, in most cases, increased δ receptor affinity. These results indicate that the & delta; receptor tolerates bulky aromatic side chains in the 3-position of cyclic β-casomorphin analogs with either δ agonist or δ antagonist properties. However, these compounds displayed drastically reduced μ receptor affinity in nearly all cases. © Munksgaard 1996. 相似文献
5.
S. Liao M. Shenderovich Z. Zhang V.J. Hruby K.E. Kvr K. Hosohata P. Davis F. Porreca H.I. Yamamura 《Chemical biology & drug design》2001,57(4):257-276
Abstract: Replacement of Phe3 in the endogenous δ‐opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β‐isopropylphenylalanine (β‐iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand‐binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [β‐iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in [β‐iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50 = 2 n m ), bioassay potency (IC50 = 1.23 n m in MVD assay) and exceptional selectivity for the δ‐opioid receptor over the µ‐opioid receptor (30 000). Further conformational studies based on two‐dimensional NMR and computer‐assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S,3R)‐β‐iPrPhe3 residues adopt trans side‐chain conformations, and the linear peptide backbone favors a distorted β‐turn conformation. 相似文献
6.
Synthesis,Biological Activity,and NMR‐Based Structural Studies of Deltorphin I Analogs Modified in Message Domain with a New α,α‐Disubstituted Glycines
下载免费PDF全文
![点击此处可从《Chemical biology & drug design》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Anika Lasota Oliwia Frączak Adriana Muchowska Michał Nowakowski Maciej Maciejczyk Andrzej Ejchart Aleksandra Olma 《Chemical biology & drug design》2016,87(6):824-832
This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)‐α‐benzyl‐β‐azidoalanine, α‐benzyl‐β‐(1‐pyrrolidinyl)alanine, α‐benzyl‐β‐(1‐piperidinyl)alanine, and α‐benzyl‐β‐(4‐morpholinyl)‐alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). The affinity of analogs containing (R) or (S)‐α‐benzyl‐β‐azidoalanine in position 3 to δ‐receptors strongly depended on the chirality of the α,α‐disubstituted residue. The conformational behavior of peptides modified with (R) or (S)‐α‐benzyl‐β‐(1‐piperidinyl)Ala, which displays the opposite selectivity, was analyzed by 1H and 13C NMR. The μ‐selective Tyr‐d ‐Ala‐(R)‐α‐benzyl‐β‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH2 lacks the helical conformation observed in the δ‐selective Tyr‐d ‐Ala‐(S)‐α‐benzyl‐β‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH2. Our results support the proposal that differences between δ‐ and μ‐selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N‐terminal message domain and the C‐terminal address domain. 相似文献
7.
Grazyna Weltrowska Thi M.‐D. Nguyen Carole Lemieux Nga N. Chung Peter W. Schiller 《Chemical biology & drug design》2008,72(5):337-340
Analogues of the opioid peptides H‐Tyr‐c[d ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 (non‐selective), H‐Tyr‐d ‐Arg‐Phe‐Lys‐NH2 (μ‐selective) and dynorphin A(1‐11)‐NH2 (κ‐selective) containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr1 were synthesized. All three Bcp1‐opioid peptides retained high μ opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr1‐containing parent peptides. The cyclic peptide H‐Bcp‐c[d ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp1‐analogue of dynorphin A(1‐11)‐NH2 displayed partial agonism at the μ receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand’s ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity. 相似文献
8.
JOËL BELLENEY BERNARD P. ROQUES MARIE-CLAUDE FOURNIE-ZALUSKI 《Chemical biology & drug design》1987,30(3):356-364
The preferential conformations of the δ selective opioid peptides DPLPE (Tyr-c[D-Pen-Gly-Phe-Pen]) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO-d6 solution. In neutral conditions, the weak NH temperature coefficients of the C-terminal residue (Pen5 or Thr6), associated with interproton NH-NH and α-NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various γ and/or β turns may account for these experimental data. A similar orientation of the N-terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable γ turn around the amino acid in position 2. Finally, a short distance, about 10 Å, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for the constrained peptide DPLPE and the flexible hexapeptide DTLET. Therefore, it may be hypothesized that the enhanced δ selectivity of DPLPE is related to a very large conformational expense of energy needed to interact with the μ opioid receptor, a feature not encountered in the case of DTLET. These findings might allow peptides to be designed retaining a high affinity for δ opioid receptors associated with a very low cross-reactivity with μ binding sites. 相似文献
9.
Abstract: A series of potential affinity label derivatives of the amphibian opioid peptide [d ‐Ala2]deltorphin I were prepared by incorporation at the para position of Phe3 (in the ‘message’ sequence) or Phe5 (in the ‘address’ sequence) of an electrophilic group (i.e. isothiocyanate or bromoacetamide). The introduction of the electrophile was accomplished by incorporating Fmoc‐Phe(p‐NHAlloc) into the peptide, followed later in the synthesis by selective deprotection of the Alloc group and modification of the resulting amine. While para substitution decreased the δ‐opioid receptor affinity, selected analogs retained nanomolar affinity for δ receptors. [d ‐Ala2,Phe(p‐NCS)3]deltorphin I exhibited moderate affinity (IC50 = 83 nm ) and high selectivity for δ receptors, while the corresponding amine and bromoacetamide derivatives showed pronounced decreases in δ‐receptor affinity (80‐ and >1200‐fold, respectively, compared with [d ‐Ala2]deltorphin I). In the ‘address’ sequence, the Phe(p‐NH2)5 derivative showed the highest δ‐receptor affinity (IC50 = 32 nm ), while the Phe(p‐NHCOCH2Br)5 and Phe(p‐NCS)5 peptides displayed four‐ and tenfold lower δ‐receptor affinities, respectively. [d ‐Ala2,Phe(p‐NCS)3]deltorphin I exhibited wash‐resistant inhibition of [3H][d ‐Pen2,D‐Pen5]enkephalin (DPDPE) binding to δ receptors at a concentration of 80 nm . [d ‐Ala2, Phe(p‐NCS)3]deltorphin I represents the first affinity label derivative of one of the potent and selective amphibian opioid peptides, and the first electrophilic affinity label derivative of an agonist containing the reactive functionality in the ‘message’ sequence of the peptide. 相似文献
10.
Grazyna Weltrowska Irena Berezowska Carole Lemieux Nga N. Chung Brian C. Wilkes Peter W. Schiller 《Chemical biology & drug design》2010,75(2):182-188
In an effort to improve the bioavailability of the non-selective, cyclic enkephalin analogues H-Dmt-c[d -Cys-Gly-Phe-d (or L )-Cys]NH2 (Dmt = 2′,6′-dimethyltyrosine), analogues N-methylated at the Phe4 and/or Cys5 residue were synthesized. In comparison with the non-methylated parent peptides, all mono- and N-di-methylated analogues in general retained high binding affinities at all three opioid receptors and high opioid agonist potencies in functional opioid activity assays. The results indicate that the progressive conformational restriction in these compounds upon mono- and di-N-methylation did not significantly affect the in vitro opioid activity profile. A low-energy conformer identified for the conformationally most restricted analogue of the series, H-Dmt-c[D -Cys-Gly-Phe(NMe)-L -Cys(NMe)]NH2 (6), showed good spatial overlap of the essential pharmacophoric moieties with those in the proposed μ receptor-bound conformation of the μ-selective opioid peptide JOM-6 [H-Tyr-c(S-Et-S)[D -Cys-Phe-D -Pen]NH2] (Pen = penicillamine) [Mosberg M.I. and Fowler C.B. (2002) J Peptide Res; 60:329–335], in agreement with the moderate μ selectivity determined for this compound. An analogue of 6 containing (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in place of Dmt1 was an opioid antagonist with quite high opioid receptor binding affinities and can be expected to show improved bioavailability because of its further increased lipophilicity and reduced hydrogen-bonding capacity. 相似文献
11.
M. Cai C. Cai A. V. Mayorov C. Xiong C. M. Cabello V. A. Soloshonok J. R. Swift D. Trivedi V. J. Hruby 《Chemical biology & drug design》2004,63(2):116-131
Abstract: To investigate the molecular basis for the interaction of the χ‐constrained conformation of melanotropin peptide with the human melanocortin receptors, a series of β‐substituted proline analogs were synthesized and incorporated into the Ac‐Nle‐c[Asp‐His‐d ‐Phe‐Arg‐Trp‐Lys]‐NH2 (MT‐II) template at the His6 and d ‐Phe7 positions. It was found that the binding affinities generally diminished as the steric bulk of the p‐substituents of the 3‐phenylproline residues increased. From (2S, 3R)‐3‐phenyl‐Pro6 to (2S, 3R)‐3‐(p‐methoxyphenyl)‐Pro6 analogs the binding affinity decreased 23‐fold at the human melanocortin‐3 receptor (hMC3R), 17‐fold at the hMC4R, and eight‐fold at the hMC5R, but selectivity for the hMC5R increased. In addition, the substitution of the d ‐Phe7 residue with a (2R, 3S)‐3‐phenyl‐Pro resulted in greatly reduced binding affinity (103–105) at these melanocortin receptors. Macromodel's Large Scale Low Mode (LLMOD) with OPLS‐AA force field simulations revealed that both MT‐II and SHU‐9119 share a similar backbone conformation and topography with the exception of the orientation of the side chains of d ‐Phe7/d ‐Nal (2′)7 in χ space. Introduction of the dihedrally constrained phenylproline analogs into the His6 position (analogs 2 – 6 ) caused topographical changes that might be responsible for the lower binding affinities. Our findings indicate that hMC3 and hMC4 receptors are more sensitive to steric effects and conformational constraints than the hMC5 receptor. This is the first example for melanocortin receptor selectivity where the propensity of steric interactions in χ space of β‐modified Pro6 analogs of MT‐II has been shown to play a critical role for binding as well as bioefficacy of melanotropins at hMC3 and hMC4 receptors, but not at the hMC5 receptor. 相似文献
12.
RONALD C. HAASETH TERESA ZALEWSKA PEG DAVIS HENRY I. YAMAMURA FRANK PORRECA VICTOR J. HRUBY 《Chemical biology & drug design》1997,50(3):171-177
Several para-substituted Phe4 analogues of the δ1-selective antagonist [l -Ala3]. DPDPE (DPADPE) were prepared and evaluated for their brain-binding and in vitro pharmacological effects. Unlike the p-haloPhe4 analogues of DPDPE and the deltorphins, similar analogues of DPADPE with electron-withdrawing groups substituted at the para-position of the Phe4 aromatic ring did not all have increased potency and selectivity for δ opioid receptors, but all retained high potency and selectivity for δ opioid receptors greater than DPDPE. © Munksgaard 1997. 相似文献
13.
Abstract: Dynorphin A (Dyn A), a 17 amino acid peptide H‐Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile‐Arg‐Pro‐Lys‐Leu‐Lys‐Trp‐Asp‐Asn‐Gln‐OH, is a potent opioid peptide which interacts preferentially with κ‐opioid receptors. Research in the development of selective and potent opioid peptide ligands for the κ‐receptor is important in mediating analgesia. Several cyclic disulphide bridge‐containing peptide analogues of Dyn A, which were conformationally constrained in the putative message or address segment of the opioid ligand, were designed, synthesized and assayed. To further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, a systematic series of Dyn A1?11‐NH2 cyclic analogues incorporating the sulphydryl‐containing amino acids l ‐ and d ‐Cys and l ‐ and d ‐Pen in positions 5 and 11 were synthesized and assayed. Cyclic lactam peptide analogues were also synthesized and assayed. Several of these cyclic analogues, retained the same affinity and selectivity (vs. the μ‐ and δ‐receptors) as the parent Dyn A1?11‐NH2 peptide in the guinea‐pig brain (GPB), but exhibited a much lower activity in the guinea‐pig ileum (GPI), thus leading to centrally vs. peripherally selective peptides. Studies of the structure–activity relationship of Dyn A peptide provide new insights into the importance of each amino acid residue (and their configurations) in Dyn A analogues for high potency and good selectivity at κ‐opioid receptors. We report herein the progress towards the development of Dyn A peptide ligands, which can act as agonists or antagonists at cell surface receptors that modulate cell function and animal behaviour using various approaches to rational peptide ligand‐based drug design. 相似文献
14.
Fuying Li Chenlei Yin Jie Chen Jinggen Liu Xin Xie Ao Zhang 《Chemical biology & drug design》2009,74(4):335-342
Mono‐ and bis‐indolomorphinans were synthesized through a multi‐step synthetic approach from the alkaloid, thebaine, to further explore the C‐ring SAR (structure‐activity relationship) of morphinan scaffold. Both mono‐indoles displayed good binding affinity and selectivity for the δ receptor, with compound 6b possessed the highest Ki value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both δ and κ receptors, but moderate binding at the μ receptor was observed. Functional assays indicated that the newly synthesized mono‐indole 6b was δ‐agonist, opposite to the δ‐antagonist profile of naltrindole. Bisindoles 7a,b were μ‐agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes. 相似文献
15.
Two peptides, designed to contain structural models of the proposed hydrophilic linker domain (residues 6-12) and amphiphilic α-helical domain (residues 13-29) in β-endorphin, have been tested for their abilities to mimic the opioid receptor selectivity profile of the natural hormone. In competitive binding assays employing guinea-pig brain membranes, both peptides displayed a much higher affinity for μ- and δ-opioid receptors than for κ opioid receptors. Relative to β-endorphin, the peptide models were 2-3 times more potent in the μ and κ receptor binding assays, and about equipotent in the δ receptor binding assay. In guinea-pig ileum assays, one peptide was equipotent to β-endorphin and the other was twice as potent. Like β-endorphin, their actions on this tissue were highly sensitive to naloxone antagonism, indicating that they were mediated by μ receptors and not κ receptors. In view of the design of the two peptide models, and their minimal homology to the natural hormone, these results provide additional evidence in support to our proposal for the functional conformation of β-endorphin. 相似文献
16.
J. Fichna J.‐C. Do‐Rego M. Mirowski J. Costentin A. Janecka 《Chemical biology & drug design》2005,65(4):459-464
Abstract: Endomorphin‐2 (Tyr‐Pro‐Phe‐Phe‐NH2) binds with high affinity and selectivity to the μ‐opioid receptor. In the present study, [125I]endomorphin‐2 has been used to characterize μ‐opioid‐binding sites on transplantable mouse mammary adenocarcinoma cells. Cold saturation experiments performed with [125I]endomorphin‐2 (1 nm ) show biphasic binding curves in Scatchard coordinates. One component represents high affinity and low capacity (Kd = 18.79 ± 1.13 nm , Bmax = 635 ± 24 fmol/mg protein) and the other shows low affinity and higher capacity (Kd = 7.67 ± 0.81 μm , Bmax = 157 ± 13 pmol/mg protein) binding sites. The rank order of agonists competing for the [125I]endomorphin‐2 binding site was [d ‐1‐Nal3]morphiceptin > endomorphin‐2 ? [d ‐Phe3]morphiceptin > morphiceptin > [d ‐1‐Nal3]endomorphin‐2, indicating binding of these peptides to μ‐opioid receptors. The uptake of 131I‐labeled peptides administered intraperitoneally to tumor‐bearing mice was also investigated. The highest accumulation in the tumor was observed for [d ‐1‐Nal3]morphiceptin, which reached the value of 8.19 ± 1.14% dose/g tissue. 相似文献
17.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(2):177-195
To date, some non‐selective β‐adrenoceptor (β‐AR) positron emission tomography (PET) radioligands are in clinical use, but no PET radioligand for the selective imaging of cardiac β1‐ARs is clinically available. Therefore, the aim of this study was to develop a potential high‐affinity PET radioligand for the β1‐subtype of ARs. Here, the synthesis and in vitro evaluation of (S)‐ and (R)‐N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐[4‐(2‐fluoro‐ethoxy)‐phenyl]‐urea ( 8a–b ), derivatives of the well‐characterized β1‐AR selective antagonist, ICI 89,406, are described. The (S)‐isomer 8a shows both higher β1‐AR selectivity and β1‐AR affinity than the (R)‐enantiomer 8b (selectivity: 40 800 vs 1580; affinity: KI1=0.049 nM vs KI1=0.297 nM). Therefore, the 18F‐labelled analogue 8e of compound 8a was synthesized. While the direct nucleophilic 18F‐fluorination of the tosylate precursor 8d produced 8e in low radiochemical yields (?2.9% decay‐corrected) and specific activities (?3.5 GBq/µmol at the end of synthesis (EOS), n=9) the alternative two‐step synthesis of 8e from ethylene glycol di‐p‐tosylate 9 , [18F]fluoride ion and phenol precursor 8f gave satisfying results (16.4±3.2% radiochemical yield (decay‐corrected), 99.7±0.5% radiochemical purity, 40±8 GBq/µmol specific activity at the EOS within 174±3 min from the end of bombardment (EOB) (n=5)). Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
18.
V. Constantinou‐Kokotou V. Magrioti T. Markidis G. Kokotos 《Chemical biology & drug design》2001,58(4):325-331
Abstract: A general method for the synthesis of enantiopure non‐natural α‐amino acids is described. The key intermediate tert‐butyl (2S)‐2‐[bis(tert‐butoxycarbonyl)amino]‐5‐oxopentanoate was obtained from l ‐glutamic acid after suitable protection and selective reduction of the γ‐methyl ester group by DIBALH. Wittig reaction of this chiral aldehyde with various ylides led to a variety of δ,ε‐unsaturated α‐amino acids. This methodology was applied to the synthesis of (S)‐2‐amino‐oleic acid. 相似文献
19.
Jan Höcker Ruwen Böhm Patrick Meybohm Matthias Gruenewald Jochen Renner Henning Ohnesorge Jens Scholz Berthold Bein 《The Journal of pharmacy and pharmacology》2009,61(7):901-910
Objectives α2‐Adrenergic and μ‐opioid receptors belong to the rhodopsin family of G‐protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with α2‐adrenoceptor‐subtypes in mice lacking one individual α2‐adrenoceptor‐subtype (α2‐adrenoceptor knockout). Methods Opioid interaction with α2‐adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α2A‐, α2B‐ or α2C‐adrenoceptor deficient mice. Displacement of the radiolabelled α2‐adrenoceptor agonist [125I]paraiodoclonidine from α2‐adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α2‐adrenoceptor subtypes in different brain regions was quantified. Key findings Morphine but not fentanyl or naloxone provoked dose‐dependent displacement of [125I]paraiodoclonidine from all α2‐adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α2A‐adrenoceptor knockout mice. Conclusions Our results indicated that morphine interacted with α2‐adrenoceptors showing higher affinity for the α2B and α2C than for the α2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α2‐adrenoceptors. This effect may have an impact on the pharmacological actions of morphine. 相似文献
20.
SANDRA C. STORY THOMAS F. MURRAY GARY E. DELANDER JANE V. ALDRICH 《Chemical biology & drug design》1992,40(2):89-96
A series of 2-substituted dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; Ki values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay. 相似文献